Born in Trondheim, Norway. He was educated in Oslo and Copenhagen. He became astudent in Biological Science in the laboratory of August Krogh in Copenhagen in 1937. Schmidt-Nielsen moved to the United States, where he studied at Swarthmore College, Stanford University, and the University of Cincinnati College of Biology.

Schmidt-Nielsen published over 275 scientific papers, received the International Prize for Biology and wrote the authoritative text on animal physiology. Schmidt-Nielsen is widely recognized as having made significant contributions to ecophysiology. He has been referred to as "the father of comparative physiology and integrative biology" and "one of the all-time greats of animal physiology". He came to Duke University in 1952 and became a James B. Duke Professor in the Department of Biology.

In 1980, Knut Schmidt-Nielsen was elected President of the International Union of Physiological Sciences. He was the founding editor of News in Physiological Sciences. He was amember of the Royal Society of London, the French Academy of Sciences and the United States National Academy of Sciences.. Next to the Biological Science building on Duke's campus is a statue of Schmidt-Nielson looking at a camel, honoring his discovery that a camel stores fat in its hump to serve as a water and energy supply.